SPOP Promotes ATF2 Ubiquitination and Degradation to Suppress Prostate Cancer Progression

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2018 Jul 13

PMID 29996942

Citations 26

Authors

Jian Ma

Kun Chang

Jingtao Peng

Qing Shi

Hualei Gan

Kun Gao

Kai Feng

Fujiang Xu

Hailiang Zhang

Bo Dai

Yao Zhu

Guohai Shi

Yijun Shen

Yiping Zhu

Xiaojian Qin

Yao Li

Pingzhao Zhang

Dingwei Ye

Chenji Wang

Affiliations

Soon will be listed here.

Abstract

Background: Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alterations. SPOP (Speckle-type POZ Protein) is one of the most frequently mutated genes in primary prostate cancer, suggesting that SPOP may be a potential driver of prostate cancer. The aim of this work was to investigate how SPOP mutations contribute to prostate cancer development and progression.

Methods: To identify molecular mediators of the tumor suppressive function of SPOP, we performed a yeast two-hybrid screen in a HeLa cDNA library using the full-length SPOP as bait. Immunoprecipitation and Western Blotting were used to analyze the interaction between SPOP and ATF2. Cell migration and invasion were determined by Transwell assays. Immunohistochemistry were used to analyze protein levels in patients' tumor samples.

Results: Here we identified ATF2 as a bona fide substrate of the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP recognizes multiple Ser/Thr (S/T)-rich degrons in ATF2 and triggers ATF2 degradation via the ubiquitin-proteasome pathway. Strikingly, prostate cancer-associated mutants of SPOP are defective in promoting ATF2 degradation in prostate cancer cells and contribute to facilitating prostate cancer cell proliferation, migration and invasion.

Conclusion: SPOP promotes ATF2 ubiquitination and degradation, and ATF2 is an important mediator of SPOP inactivation-induced cell proliferation, migration and invasion.

Citing Articles

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SPOP-mediated RIPK3 destabilization desensitizes LPS/sMAC/zVAD-induced necroptotic cell death.

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The role of protein post-translational modifications in prostate cancer.

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